Increased risk of cardiovascular events under the treatments with Janus kinase inhibitors versus biological disease-modifying antirheumatic drugs in patients with rheumatoid arthritis: a retrospective longitudinal population-based study using the Japanese health insurance database.

OBJECTIVES: To compare the risk of cardiovascular events among Janus kinase inhibitors (JAKIs), biological disease-modifying antirheumatic drugs (bDMARDs) (tumour necrosis factor inhibitors (TNFIs) and non-TNFIs) and methotrexate (MTX) in Japanese patients with rheumatoid arthritis (RA). METHODS: Using Japanese claims data, patients with RA were enrolled in this study if they had at least one ICD-10 code (M05 or M06), were new users of JAKIs, bDMARDs or MTX between July 2013 and July 2020 and being 18 years old or older. The incidence rate (IR), IR ratio and adjusted hazard ratio (aHR (95% CI)) of cardiovascular events including venous thromboembolism, arterial thrombosis, acute myocardial infarction and stroke were calculated. A time-dependent Cox regression model adjusted for patient characteristics at baseline was used to calculate aHR. RESULTS: In 53 448 cases, IRs/1000 patient-years of the overall cardiovascular events were 10.1, 6.8, 5.4, 9.1 and 11.3 under the treatments with JAKIs, bDMARDs, TNFIs, non-TNFIs and MTX, respectively. The adjusted HRs of JAKIs for overall cardiovascular events were 1.7 (1.1 to 2.5) versus TNFIs without MTX and 1.7 (1.1 to 2.7) versus TNFIs with MTX. CONCLUSIONS: Among patients with RA, individuals using JAKIs had a significantly higher risk of overall cardiovascular events than TNFIs users, which was attributed to the difference in the risk between JAKIs and TNFIs versus MTX. These data should be interpreted with caution because of the limitations associated with the claims database.

Cost-consequence of abatacept as first-line therapy in Japanese rheumatoid arthritis patients using IORRA real-world data.

OBJECTIVES: To investigate the cost-effectiveness of abatacept (ABA) as first-line (1L) therapy in Japanese rheumatoid arthritis (RA) patients using data from the Institute of Rheumatology, Rheumatoid Arthritis database. METHODS: A decision-analytic model was used to estimate the cost per American College of Rheumatology response of at least 50% improvement (ACR50) responder and per patient in Clinical Disease Activity Index (CDAI) and Simplified Disease Activity Index (SDAI) remission from a Japanese healthcare payers' perspective over a 2-year time horizon. Clinical characteristics of patients on ABA-1L were matched with those of patients on ABA second or later line (2L+) or tumour necrosis factor inhibitor (TNFi)-1L directly or using propensity scores. Resource utilisation and medical costs were calculated from the Japan Medical Data Center claims database. Parameter uncertainty was addressed by sensitivity and subgroup analyses (age, treatment duration, Japanese version of Health Assessment Questionnaire [J-HAQ] score). RESULTS: Incremental costs per member per month (ΔPMPM) for ABA-1L versus TNFi-1L and ABA-2L+ were -1,571 Japanese Yen (JPY) and 81 JPY, respectively. For ABA-1L versus TNFi-1L, ΔPMPM by ACR50 response was -11,715 JPY and by CDAI and SDAI remission 11,602 JPY and 47,003 JPY, respectively. Corresponding costs for ABA-1L were lower for all outcome parameters versus those for ABA-2L+. Scenario analyses showed that ABA-1L was cost-effective over TNFi-1L in patients <65 years for any outcome. Furthermore, ABA-1L was cost-effective over ABA-2L+ for all outcomes in patients with age <65 years, disease duration <5 years and J-HAQ ≥1.5. CONCLUSIONS: ABA-1L demonstrated a favourable cost-effectiveness profile in RA patients, accruing savings for the Japanese healthcare payers.

Geographic variations in rheumatoid arthritis treatment in Japan: A nationwide retrospective study using the national database of health insurance claims and specific health checkups of Japan.

OBJECTIVES: To characterize the treatments for rheumatoid arthritis (RA) among institution types and prefectures in Japan. METHODS: Using the National Database of Health Insurance Claims and Specific Health Checkups of Japan in the 2017 fiscal year, we investigated disease-modifying antirheumatic drug (DMARD) and oral corticosteroid prescription trends across 825 thousand RA patients. These data were compared between specialized and non-specialized institutions and by prefecture. RA specialized institutions (SIs) were defined as either institutions registered in the rheumatology training program at the Japan College of Rheumatology or institutions where board-certified rheumatologists were employed. RESULTS: The overall percentage of patients who never visited an SI was 31.8% and increased with age (16-29 years old = 15.6%; ≥80 years = 42.8%). In twelve prefectures (25.5%), the proportions of patients who never visited an SI were at least 10% higher than the overall average. The proportions of patients who only visited SIs and were prescribed methotrexate and biological DMARDs were ranged from 51.9-72.9% and 19.5-33.2%, respectively. However, those of patients who had never visited an SI and were prescribed those medications were 44.0-71.6% and 7.2-28.0%, respectively. CONCLUSIONS: This is the first study evaluating the trends in RA treatments by prefecture and institution specialty by using the NDB Japan. Opportunities of patients with RA for visiting SI was unevenly distributed in Japan, affecting some aspects of treatment provided.

Trends in actual medication use for child-onset systemic lupus erythematosus using the Japanese health insurance database 2009-18.

OBJECTIVES: Immunosuppressive therapy is the mainstay of treatment for child-onset systemic lupus erythematosus (cSLE). Since epidemiological data on Japanese cSLE patients are not available, we evaluated the trends in how treatment choices have changed over time in Japan. METHODS: Using the Japanese health insurance database provided by Medical Data Vision Co., Ltd, we identified cSLE patients and evaluated changes in the use of corticosteroids and immunosuppressive medications and maximum daily doses of prednisolone from 2009 to 2018. RESULTS: Of 182 cSLE patients, 86% were female, and the median age was 14 years. Oral prednisolone was used in more than 97% of cSLE patients during the study period, and the median of the maximum daily dose in each patient decreased over time. Intravenous cyclophosphamide was used less frequently after 2016, while mycophenolate mofetil and hydroxychloroquine were used frequently after 2016. The use of mizoribine reduced after 2014, whereas the other immunosuppressive medications showed no significant change over time; the use of biological agents was very limited. CONCLUSIONS: Oral prednisolone was the mainstay of treatment for cSLE, and the maximum daily dose has reduced over the past decade. The most frequently prescribed immunosuppressive therapy has shifted to mycophenolate mofetil over time.

Management of End-stage Renal Disease Associated with Systemic Rheumatic Diseases.

The outcomes of rheumatic diseases (RDs) have improved over the past decades. However, a significant proportion of the patients still suffer from end-stage renal disease (ESRD) and have to bear the burden of hemodialysis. It is crucial to prevent patients with RDs from developing ESRD from viewpoints of medicine and medical economics. For those who already have ESRD, it is important to improve vial prognosis and quality of life through appropriate management of disease activity and comorbidities related to ESRD. Thus, rheumatologists and nephrologists need to recognize risk factors associated with progression to ESRD along with their appropriate management. Although the activity of most RDs tends to decrease after initiation of hemodialysis, disease activity may still increase, and recognizing how to appropriately use immunosuppressive agents even after the development of ESRD is crucial. The treatment of RDs needs extra attention as hydroxychloroquine requires more frequent monitoring for adverse drug reactions; therapeutic drug monitoring is necessary for mycophenolate mofetil, cyclosporine A, and tacrolimus; cyclophosphamide and azathioprine need dose adjustments; methotrexate and bucillamine are contraindicated in patients with ESRD; leflunomide and sulfasalazine do not require significant dose reduction and iguratimod should be carefully administered. The pharmacokinetics of biological agents such as rituximab or belimumab are not affected by ESRD, and dose adjustments are not necessary. Collaboration between rheumatologists and nephrologists is needed more than ever and is expected to produce a complementary effect and achieve better outcomes in clinical settings, although this cooperation has not always been conducted appropriately.

Prevalence of patients with rheumatoid arthritis and age-stratified trends in clinical characteristics and treatment, based on the National Database of Health Insurance Claims and Specific Health Checkups of Japan.

AIM: To estimate the prevalence and age-stratified treatment trends and clinical characteristics of rheumatoid arthritis (RA) in Japan. METHOD: Using 7 RA definitions, the prevalence of RA in those aged ≥16 years was estimated using the National Database of Health Insurance Claims and Specific Health Checkups of Japan in the fiscal year 2017. We analyzed age-stratified trends in characteristics and treatments. RESULTS: Of 1 116 122 patients aged ≥16 years with at least 1 RA-related International Classification of Diseases-10 code, 825.7 thousand patients (women, 76.3%) were assessed as having RA with an estimated prevalence of 0.65%. The highest age-stratified prevalence was 1.63% in patients aged 70-79 years. Overall, 60.8% and 7.0% of patients with RA were aged ≥65 years and ≥85 years, respectively. Methotrexate use was most frequent in patients aged 50-59 years (73.0%) and least frequent in patients aged ≥85 years (38.2%). Biologic disease-modifying antirheumatic drugs use was 50.9% in patients aged 16-19 years and decreased to 13.7% in those aged ≥85 years. Preference for the use of tumor necrosis factor inhibitors versus abatacept decreased from 24.0:1 to 1.7:1 in patients aged 16-19 years and ≥85 years, respectively. The prevalence of cardiovascular disease was 3.5% in patients aged 60-69 years and 12.1% in those aged ≥85 years. Overall RA-related orthopedic surgeries were most prevalent in patients aged 70-79 years. CONCLUSION: The estimated prevalence of patients with RA in Japan was 0.65%. Age-stratified treatment trends and clinical characteristics have been described in a super-aged society for the first time.

A large observational cohort study of rheumatoid arthritis, IORRA: Providing context for today's treatment options.

Real-world evidence, based on real-world data from routine clinical treatment, is becoming increasingly important for providing high-quality medical care. Large-scale cohort studies can provide useful access to some of this real-world evidence, as shown by the IORRA (Institute of Rheumatology, Rheumatoid Arthritis) cohort in Japan. This large cohort study of patients with rheumatoid arthritis (RA) has been surveying enrolled participants since its inception in 2000. In the last 19 years, it has served as a database for a wide range of research in areas including transitions in medical care at the clinical level, changes in therapeutic drugs, approaches to comorbidities, developments in pharmacoeconomics, and the effects of genomic information on treatment options. This research has resulted in the publication of 133 articles in English to date. IORRA monitors changes in the management of RA, and has quantified over time the daily experience of clinicians who provide routine medical care. Such observational databases, which reflect the reality of daily clinical practice, will become increasingly important and may provide a model for similar research in other disease areas.

International descriptive study for comparison of treatment patterns in patients with knee osteoarthritis between Korea and Japan using claims data.

AIM: To compare medication prescriptions for patients with knee osteoarthritis (KOA) in the real world in Korea and Japan. METHODS: This retrospective and descriptive population-based study was conducted using claims data provided by Health Insurance Review and Assessment in Korea and JMDC Inc in Japan. We defined individuals as KOA patients if they had an International Classification of Diseases 10 (ICD10) code for gonarthrosis (M17) and were ≥50 years old in 2012. Korean and Japanese patients were matched for age and sex using frequency matching. Patients were observed for 1 year from the first month of the ICD10 code M17 in 2012. We described baseline characteristics including prevalence of comorbidities, and use of medication for KOA during the observational period. RESULTS: The median age was 59 and the percentage of women was 61.4 in both countries (N = 1 133 138 in Korea, N = 10 498 in Japan). The prevalence of nonsteroidal anti-inflammatory drug (NSAID) usage in Japan (74.7%) was significantly higher than that in Korea (59.0%). Analgesics such as acetaminophen and symptomatic slow-acting drugs for OA (SYSADOA) were significantly more frequently used in Korea (25.8%) than in Japan (9.4%). Intra-articular injection (IAI) of corticosteroids or hyaluronic acid was performed more frequently in Japanese patients (57.3%) than Korean patients (30.5%). CONCLUSIONS: Medication patterns for KOA in Korea and Japan are described for the first time. Use of NSAIDs and IAI were more common in Japan, while other pain killers and SYSADOA were more commonly prescribed in Korea.

Higher risk of hospitalized infection, cardiovascular disease, and fracture in patients with rheumatoid arthritis determined using the Japanese health insurance database.

Objective: To evaluate the risk of hospitalized infection (HI), cardiovascular disease (CVD), stroke, and fracture in rheumatoid arthritis (RA) patients compared with non-RA patients using the Japanese health insurance database. Method: Among individuals aged ≥18 years, RA cases were defined to have one RA diagnostic code and receiving ≥1 disease-modifying antirheumatic drug between 2005 and 2013 (n = 6,712). Age-, sex-, calendar year of the observation start-, and observation length-matched non-RA cases were selected at 1:5 (n = 33,560). Hazard ratios (HRs) were calculated using the time-dependent Cox regression analysis. Results: Median age of the patients was 52.0 years. The incidence rates of HI, CVD, and fracture in the RA group were 2.42/100 person-years (PY), 4.94/1,000 PY, and 10.59/1,000 PY. The crude incidence rate ratios (95% CI) (RA vs. non-RA) for HI, CVD, and fracture were 2.47 (2.20-2.77), 1.89 (1.49-2.41), and 3.35 (2.80-4.02). The adjusted HR (95% CI) (RA vs. non-RA) was significantly elevated (HI, 1.74 [1.52-1.99], CVD, 1.38 [1.04-1.85], and fracture, 1.88 (1.54-2.31)]. Conclusion: The relatively young RA population had significantly higher risks of these complications than the non-RA, indicating importance of prevention of them even at young ages in clinical settings.

Targeting Low Disease Activity in Elderly-Onset Rheumatoid Arthritis: Current and Future Roles of Biological Disease-Modifying Antirheumatic Drugs.

Elderly rheumatoid arthritis (RA) is classified into two clinical subsets, elderly-onset RA (EORA) and younger-onset elderly RA. With the improvement of life expectancy in the general population and advent of the super-aging society, the number of patients with EORA is anticipated to increase. Both large and small joints are affected initially at onset, and individuals with early EORA have higher scores of disease activity and levels of acute-phase reactants than those with early younger-onset RA. EORA is a progressive disease similar to younger-onset RA. Tumor necrosis factor (TNF) inhibitors are equally or slightly less effective in elderly patients than in younger patients with RA, and disease duration may have a greater impact on disease outcomes than age. Evidence of non-TNF biological disease-modifying antirheumatic drug use in EORA is limited. TNF inhibitors may not increase the risk for infection in elderly patients any more than methotrexate; however, increasing age is an independent and strong risk factor for serious infections in patients with RA. Treatment choice in patients with EORA is strongly influenced by comorbidities, especially cardiovascular disease, chronic lung disease, and frailty. To prevent progression to irreversible geriatric syndromes, non-frail patients with EORA, who are aging successfully should undergo intensive treatment using the treat-to-target strategy, and pre-frail and frail patients with EORA should be treated with the aim of returning to a non-frail or pre-frail stage, respectively. An appropriate treatment strategy for EORA and younger-onset elderly RA should be developed in the next decade using a multi-disciplinary approach.

High prevalence of cardiovascular comorbidities in patients with rheumatoid arthritis from a population-based cross-sectional study of a Japanese health insurance database.

OBJECTIVE: To reveal any association between rheumatoid arthritis (RA) and cardiovascular comorbidities using a Japanese health insurance database. METHOD: This population-based cross-sectional study was conducted using health insurance data provided by the Japan Medical Data Center Co., Ltd. We identified 2762 RA subjects having RA diagnostic codes (ICD10 codes; M05, M060, M062-63, M068-069) with at least two physician visits more than two months apart between June 2011 and May 2012 (RA group, n = 2762). We selected age- (±5 years), sex-, and study period-matched non-RA subjects (non-RA group, n = 27,620). We compared the prevalence of cardiovascular and related comorbidities (ischemic heart diseases [IHD], cerebral infarction, hypertension [HT], dyslipidemia [DL], and diabetes mellitus [DM]) between these groups and investigated the association between RA and cardiovascular comorbidities using a conditional logistic regression analysis. RESULTS: The prevalence of all the investigated comorbidities in the RA group was significantly higher compared to the non-RA group. Odds ratios [95% confidence interval] of RA for IHD and cerebral infarction were 2.0 [1.5-2.5] and 3.1 [2.2-4.2] respectively, after adjusting for HT, DL, and DM. CONCLUSIONS: This study revealed for the first time in the Japanese population that RA was significantly associated with cardiovascular comorbidities.

Assessment of risks of pulmonary infection during 12 months following immunosuppressive treatment for active connective tissue diseases: a large-scale prospective cohort study.

OBJECTIVE: Pulmonary infections (PI) are leading causes of death in patients with connective tissue diseases (CTD). The PREVENT study (Pulmonary infections in patients REceiving immunosuppressiVE treatmeNT for CTD) assessed risk of PI in patients with active CTD in the contemporary era of advanced immunosuppressive therapy. METHODS: In patients who started corticosteroids (n = 763), conventional immunosuppressants or biologics for active CTD were enrolled. Clinical and laboratory data, usage of drugs, and occurrence of PI were collected for 12 months. Baseline risk factors were investigated using Cox regression analysis. A nested case-control (NCC) study was performed with 1:2 matched case-control pairs to assess the risk for each drug category. RESULTS: During the observation period, 32 patients died (4.2%) and 66 patients were lost to followup (8.6%). Patients with PI (n = 61, 8%) had a significantly worse accumulated survival rate than patients without (p < 0.01). Cox hazard regression analysis using baseline data showed that these factors were significantly associated with PI: age ≥ 65 years (HR 3.87, 95% CI 2.22-6.74), ≥ 20 pack-years of smoking (2.63, 1.37-5.04), higher serum creatinine level (1.21, 1.05-1.41 per 1.0 mg/dl increase), and maximum prednisolone (PSL) dose during the first 2 weeks of treatment (2.81, 1.35-5.86 per 1.0 mg/kg/day increase). Logistic regression analysis by an NCC study revealed that maximum PSL dose within 14 days before PI (OR 4.82, 95% CI 1.36-17.01 per 1.0 mg/dl increase; 2.57, 1.28-5.16 if ≥ 0.5 mg/kg/day) was significantly associated with the events, while other immunosuppressants were not. CONCLUSION: Physicians should be aware of the higher risks for corticosteroids of PI than other immunosuppressants and assess these risk factors before immunosuppressive treatment, to prevent PI.